Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel
Figure 7
Snapshots from the umbrella simulations are shown that represent important points in the PMF for benzocaine (A–D) and phenytoin (E–H).
The global minimum for each drug is at the activation gate (A,E), and the drug positions here replicate the binding poses seen in the equilibrium simulations. The same is true for the second minimum (B, F), which shows binding in the fenestration. A further hydrophobic pocket supports the drugs in the outer fenestration (C,G). At the external entrance to the fenestrations, the drugs have to pass the bulky phenylalanine residue (orange) and are at their most dehydrated creating the largest barrier in the pathway (D,H). Example snapshots show that even at this point water chains extending to the channel lumen are sometimes present.